Augmentin Chewable Tablets

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Augmentin Chewable Tablets

CLINICAL PHARMACOLOGY

Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal
tract after oral administration of AUGMENTIN. Dosing in the fasted or fed state
has minimal effect on the pharmacokinetics of amoxicillin. While AUGMENTIN can
be given without regard to meals, absorption of clavulanate potassium when taken
with food is greater relative to the fasted state. In 1 study, the relative
bioavailability of clavulanate was reduced when AUGMENTIN was dosed at 30 and
150 minutes after the start of a high-fat breakfast. The safety and efficacy
of AUGMENTIN have been established in clinical trials where AUGMENTIN was taken
without regard to meals.

*Administered at the start of a light meal.
† Mean values of 28 normal volunteers. Peak concentrations
occurred approximately 1 hour after the dose.

Oral administration of 5 mL of 250 mg/5 mL suspension of AUGMENTIN or the equivalent
dose of 10 mL of 125 mg/5 mL suspension of AUGMENTIN provides average peak serum
concentrations approximately 1 hour after dosing of 6.9 mcg/mL for amoxicillin
and 1.6 mcg/mL for clavulanic acid. The areas under the serum concentration
curves obtained during the first 4 hours after dosing were 12.6 mcg.hr/mL for
amoxicillin and 2.9 mcg.hr/mL for clavulanic acid when 5 mL of 250 mg/5 mL suspension
of AUGMENTIN or equivalent dose of 10 mL of 125 mg/5 mL suspension of AUGMENTIN
was administered to adult volunteers. One 250-mg chewable tablet of AUGMENTIN
or two 125-mg chewable tablets of AUGMENTIN are equivalent to 5 mL of 250 mg/5
mL suspension of AUGMENTIN and provide similar serum levels of amoxicillin and
clavulanic acid.

Amoxicillin serum concentrations achieved with AUGMENTIN are similar to those
produced by the oral administration of equivalent doses of amoxicillin alone.
The half-life of amoxicillin after the oral administration of AUGMENTIN is 1.3
hours and that of clavulanic acid is 1.0 hour. Time above the minimum inhibitory
concentration of 1.0 mcg/mL for amoxicillin has been shown to be similar after
corresponding q12h and q8h dosing regimens of AUGMENTIN in adults and children.

Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of
the clavulanic acid are excreted unchanged in urine during the first 6 hours
after administration of 10 mL of 250 mg/5 mL suspension of AUGMENTIN.

Concurrent administration of probenecid delays amoxicillin excretion but does
not delay renal excretion of clavulanic acid.

Neither component in AUGMENTIN is highly protein-bound; clavulanic acid has
been found to be approximately 25% bound to human serum and amoxicillin approximately
18% bound.

Amoxicillin diffuses readily into most body tissues and fluids with the exception
of the brain and spinal fluid. The results of experiments involving the administration
of clavulanic acid to animals suggest that this compound, like amoxicillin,
is well distributed in body tissues.

Two hours after oral administration of a single 35 mg/kg dose of suspension
of AUGMENTIN to fasting children, average concentrations of 3.0 mcg/mL of amoxicillin
and 0.5 mcg/mL of clavulanic acid were detected in middle ear effusions.

Microbiology: Amoxicillin is a semisynthetic antibiotic with a broad
spectrum of bactericidal activity against many gram-positive and gram-negative
microorganisms. Amoxicillin is, however, susceptible to degradation by β-lactamases,
and therefore, the spectrum of activity does not include organisms which produce
these enzymes. Clavulanic acid is a β-lactam, structurally related to the
penicillins, which possesses the ability to inactivate a wide range of β-lactamase
enzymes commonly found in microorganisms resistant to penicillins and cephalosporins.
In particular, it has good activity against the clinically important plasmid-mediated
β-lactamases frequently responsible for transferred drug resistance.

The formulation of amoxicillin and clavulanic acid in AUGMENTIN protects amoxicillin
from degradation by β-lactamase enzymes and effectively extends the antibiotic
spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin
and other β-lactam antibiotics. Thus, AUGMENTIN possesses the distinctive
properties of a broad-spectrum antibiotic and a β-lactamase inhibitor.

Amoxicillin/clavulanic acid has been shown to be active against most strains
of the following microorganisms, both in vitro and in clinical infections as
described in INDICATIONS AND USAGE.

Gram-Positive Aerobes

Staphylococcus aureus (β-lactamase and non-β-lactamase-producing)§

Gram-Negative Aerobes

Enterobacter species (Although most strains of Enterobacter species
are resistant in vitro, clinical efficacy has been demonstrated with AUGMENTIN
in urinary tract infections caused by these organisms.) Escherichia coli (β-lactamase and non-β-lactamase-producing)
Haemophilus influenzae (β-lactamase and non-β-lactamase-producing)
Klebsiella species (All known strains are β-lactamase-producing.)
Moraxella catarrhalis (β-lactamase and non-β-lactamase-producing)

The following in vitro data are available, but their clinical significance
is unknown.

Amoxicillin/clavulanic acid exhibits in vitro minimal inhibitory concentrations
(MICs) of 2 mcg/mL or less against most ( ≥ 90%) strains of Streptococcus
pneumoniae; MICs of 0.06 mcg/mL or less against most ( ≥ 90%)
strains of Neisseria gonorrhoeae; MICs of 4 mcg/mL or less against most
( ≥ 90%) strains of staphylococci and anaerobic bacteria; MICs of 8 mcg/mL
or less against most ( ≥ 90%) strains of other listed organisms. However, with
the exception of organisms shown to respond to amoxicillin alone, the safety
and effectiveness of amoxicillin/clavulanic acid in treating clinical infections
due to these microorganisms have not been established in adequate and well-controlled
clinical trials.

Anaerobic Bacteria

Susceptibility Testing

Dilution Techniques:Quantitative methods are used to determine
antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria
to antimicrobial compounds. The MICs should be determined using a standardized
procedure. Standardized procedures are based on a dilution method1
(broth or agar) or equivalent with standardized inoculum concentrations and
standardized concentrations of amoxicillin/clavulanate potassium powder.

The recommended dilution pattern utilizes a constant amoxicillin/clavulanate
potassium ratio of 2 to 1 in all tubes with varying amounts of amoxicillin.
MICs are expressed in terms of the amoxicillin concentration in the presence
of clavulanic acid at a constant 2 parts amoxicillin to 1 part clavulanic acid.
The MIC values should be interpreted according to the following criteria:

† † Staphylococci
which are susceptible to amoxicillin/clavulanic acid but resistant to
methicillin/oxacillin must be considered as resistant.

For S. pneumoniae from non-meningitis sources: Isolates should
be tested using amoxicillin/clavulanic acid and the following criteria should
be used: MIC (mcg/mL) Interpretation

MIC (mcg/mL)

Interpretation

≤ 2/1

Susceptible(S)

4/2

Intermediate(I)

≥ 8/4

Resistant(R)

Note: These interpretive criteria are based on the recommended doses
for respiratory tract infections.

A report of “Susceptible” indicates that the pathogen is likely
to be inhibited if the antimicrobial compound in the blood reaches the concentration
usually achievable. A report of “Intermediate” indicates that the
result should be considered equivocal, and, if the microorganism is not fully
susceptible to alternative, clinically feasible drugs, the test should be repeated.
This category implies possible clinical applicability in body sites where the
drug is physiologically concentrated or in situations where high dosage of drug
can be used. This category also provides a buffer zone that prevents small uncontrolled
technical factors from causing major discrepancies in interpretation. A report
of “Resistant” indicates that the pathogen is not likely to be inhibited
if the antimicrobial compound in the blood reaches the concentrations usually
achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control
microorganisms to control the technical aspects of the laboratory procedures.
Standard amoxicillin/clavulanate potassium powder should provide the following
MIC values:

Microorganism

MIC Range (mcg/mL)‡‡

E. coli ATCC 25922

2 to 8

E. coli ATCC 35218

4 to 16

E. faecalis ATCC 29212

0.25 to 1.0

H. influenzae ATCC 49247

2 to 16

S. aureus ATCC 29213

0.12 to 0.5

S. pneumoniae ATCC 49619

0.03 to 0.12

‡‡Expressed as concentration
of amoxicillin in the presence of clavulanic acid at a constant 2 parts
amoxicillin to 1 part clavulanic acid.

Diffusion Techniques: Quantitative methods that require measurement
of zone diameters also provide reproducible estimates of the susceptibility
of bacteria to antimicrobial compounds. One such standardized procedure2
requires the use of standardized inoculum concentrations. This procedure uses
paper disks impregnated with 30 mcg of amoxicillin/clavulanate potassium (20
mcg amoxicillin plus 10 mcg clavulanate potassium) to test the susceptibility
of microorganisms to amoxicillin/clavulanic acid.

Reports from the laboratory providing results of the standard single-disk susceptibility
test with a 30-mcg amoxicillin/clavulanate potassium (20 mcg amoxicillin plus
10 mcg clavulanate potassium) disk should be interpreted according to the following
criteria:

§§ Staphylococci which are resistant
to methicillin/oxacillin must be considered as resistant to amoxicillin/clavulanic
acid. a A broth microdilution method should be used for testing H.
influenzae. Beta-lactamase-negative, ampicillin-resistant strains
must be considered resistant to amoxicillin/clavulanic acid.b Susceptibility of S. pneumoniae should be determined
using a 1-mcg oxacillin disk. Isolates with oxacillin zone sizes of ≥ 20
mm are susceptible to amoxicillin/clavulanic acid. An amoxicillin/clavulanic
acid MIC should be determined on isolates of S. pneumoniae with
oxacillin zone sizes of ≤ 19 mm. c A broth microdilution method should be used for testing N.
gonorrhoeae and interpreted according to penicillin breakpoints.

Interpretation should be as stated above for results using dilution techniques.
Interpretation involves correlation of the diameter obtained in the disk test
with the MIC for amoxicillin/clavulanic acid.

As with standardized dilution techniques, diffusion methods require the use
of laboratory control microorganisms that are used to control the technical
aspects of the laboratory procedures. For the diffusion technique, the 30-mcg
amoxicillin/clavulanate potassium (20mcg amoxicillin plus 10mcg
clavulanate potassium) disk should provide the following zone diameters in these
laboratory quality control strains:

Microorganism

Zone Diameter (mm)

E. coli ATCC 25922

19 to 25 mm

E. coli ATCC 35218

18 to 22 mm

S. aureus ATCC 25923

28 to 36 mm

Clinical Studies

In pediatric patients (aged 2 months to 12 years), 1 US/Canadian clinical trial
was conducted which compared 45/6.4 mg/kg/day (divided q12h) of AUGMENTIN for
10 days versus 40/10 mg/kg/day (divided q8h) of AUGMENTIN for 10 days in the
treatment of acute otitis media. Only the suspension formulations were used
in this trial. A total of 575 patients were enrolled, with an even distribution
among the 2 treatment groups and a comparable number of patients were evaluable
(i.e., ≥ 84%) per treatment group. Strict otitis media-specific criteria were
required for eligibility and a strong correlation was found at the end of therapy
and follow-up between these criteria and physician assessment of clinical response.
The clinical efficacy rates at the end of therapy visit (defined as 2-4 days
after the completion of therapy) and at the follow-up visit (defined as 22-28
days post-completion of therapy) were comparable for the 2 treatment groups,
with the following cure rates obtained for the evaluable patients: At end of
therapy, 87.2% (n = 265) and 82.3% (n = 260) for 45 mg/kg/day q12h and 40 mg/kg/day
q8h, respectively. At follow-up, 67.1% (n = 249) and 68.7% (n = 243) for 45
mg/kg/day q12h and 40 mg/kg/day q8h, respectively.

The incidence of diarrhea† † † was significantly
lower in patients in the q12h treatment group compared to patients who received
the q8h regimen (14.3% and 34.3%, respectively). In addition, the number of
patients with either severe diarrhea or who were withdrawn with diarrhea was
significantly lower in the q12h treatment group (3.1% and 7.6% for the q12h/10
day and q8h/10 day, respectively). In the q12h treatment group, 3 patients (1.0%)
were withdrawn with an allergic reaction, while 1 patient (0.3%) in the q8h
group was withdrawn for this reason. The number of patients with a candidal
infection of the diaper area was 3.8% and 6.2% for the q12h and q8h groups,
respectively.

It is not known if the finding of a statistically significant reduction in
diarrhea with the oral suspensions dosed q12h, versus suspensions dosed q8h,
can be extrapolated to the chewable tablets. The presence of mannitol in the
chewable tablets may contribute to a different diarrhea profile. The q12h oral
suspensions are sweetened with aspartame only.

REFERENCES

† † † Diarrhea was defined
as either: (a) 3 or more watery or 4 or more loose/watery stools in 1 day; OR
(b) 2 watery stools per day or 3 loose/watery stools per day for 2 consecutive
days.

§ Staphylococci which are resistant to methicillin/oxacillin
must be considered resistant to amoxicillin/clavulanic acid.

|| Because amoxicillin has greater in vitro activity against
S.pneumoniae than does ampicillin or penicillin, the majority
of S. pneumoniae strains with intermediate susceptibility to ampicillin
or penicillin are fully susceptible to amoxicillin.

¶ Adequate and well-controlled clinical trials
have established the effectiveness of amoxicillin alone in treating certain
clinical infections due to these organisms.

** These are non-β-lactamase-producing organisms,
and therefore, are susceptible to amoxicillin alone.